The hormone angiotensin II is recognized as the most potent vasopressor agent that produces hypertension in mammals. The action of the enzyme renin on the plasma protein substrate angiotensinogen results in the production of an inactive decapeptide, angiotensin I, which, upon conversion by the nonselective angiotensin converting enzyme (ACE) provides angiotensin II, the active hormone. See, e.g., Regoli et al., Pharm. Rev., 26, 69 (1974). Angiotensin II causes vasoconstriction and stimulates aldosterone secretion (from the adrenal gland) which results in a rise of both blood volume and pressure. Angiotensin II also can act on other organs such as the brain (Fitzsimmons, Rev. Physiol. Biochem. Pharmacol., 87, 117, (1980)), and a variety of glandular tissues including the kidney, liver and ovaries. Angiotensin II may also have a role in regulating the rate of cell growth and differentiation. See, e.g., Naftilan et al., J. Clin. Invest., 83, 1419 (1989), and Jackson et al., Nature, 335, 437 (1988).
Some antihypertensive agents act as inhibitors of ACE thus blocking the formation of angiotensin II and its resulting increase of blood pressure. More recently, both peptide and non-peptide antagonists of angiotensin II have been disclosed--see, e.g., EPO Patent Application Publication 253310 and references contained therein, and Chill et al., J. Pharmacol. Exp. Ther., 250, 867 (1989).
The present invention provides novel, potent, and effective compounds that antagonize angiotensin II at receptor sites in the body and are therefore useful as antihypertensive agents and for the treatment of congestive heart failure . (Douglas, W. W., in The Pharmacological Basis of Therapeutics, 7th Edition, Eds. A. G. Gilman, L. S. Goodman, T. W. Roll and F. Murod, MacMillan Publishing Co., New York, 1985) p. 652.